Robot-Assisted Urological Oncology Procedures, Outcomes, and Safety in Frail Patients: A Narrative Review of Available Studies

In this study, we assess the impact of frailty on the success rate and risk of complications of robot-assisted urological procedures and introduce effective preoperative screening tools to evaluate frail patients’ fitness to tolerate robot-assisted urological surgery. We performed a search of electronic databases for available studies, published up to August 2023, investigating the outcomes of robot-assisted urological oncology procedures and their safety in frail patients. Sixteen studies were ultimately selected, investigating the implications of frailty in robot-assisted radical cystectomy, robot-assisted partial nephrectomy, and robot-assisted radical prostatectomy. All the studies used the Clavien–Dindo classification of complications with serious complications considered as Clavien–Dindo ≥3. Frail patients significantly benefit from robot-assisted urological procedures in comparison to open surgery, with lower rates of blood transfusion and a shorter length of stay. However, they also have a higher risk of postoperative complications than non-frail patients, as well as increased rates of conversion to open, total hospital costs, and in-hospital mortality after robot-assisted procedures. Robot-assisted urological procedures can improve the postoperative recovery of frail patients in comparison to open surgery. Reliable frailty indexes such as the Johns Hopkins indicator and simplified frailty index, as well as the Geriatric 8 screening tool, should be routinely used in the preoperative assessment of frail patients to optimize surgical decision-making.


Introduction
The progressive increase in life expectancy in developed countries has been associated with higher rates of urological malignancies in elderly patients.It is well established that old age is a risk factor for worse recovery after surgery.However, in recent years, frailty has emerged as a more accurate indicator of patients' health and the outcome of invasive procedures.Frailty is a syndrome that includes multiple factors such as a decline in physical strength, endurance, mobility, and loss of weight, mainly affecting the geriatric population.It is associated with a higher risk of complications after oncological procedures and all-cause mortality. 1,2[3][4][5][6] Besides, the benefits of RARC and intracorporeal urinary diversion concerning the need for blood transfusion and almost all health-related quality of life domains in comparison to open surgery have been proven recently with high-quality randomized control trials. 7,8kolaos Kostakopoulos 1,2 Themistoklis Bellos 3 Evangelos Malovrouvas 1

Stamatios Katsimperis 3
Athanasios Kostakopoulos 1 1 Department of Urology, Metropolitan General, Athens, Greece In this review article, we investigate the safety and outcomes of robotic-assisted urological procedures in frail patients and demonstrate the most effective preoperative screening tools to assess these patients' fitness to tolerate minimally invasive urological surgery.

Material and Methods
We searched the available literature, using the MEDLINE (via PubMed), Web of Science, and the Cochrane Library databases for studies published up to August 2023, investigating the impact of frailty on the outcomes and risk of complications of robot-assisted urological procedures, as well as identifying the most accurate frailty indexes for the preoperative assessment of patients, using suitable keywords: "robotic urological procedures," "frailty, " "robotic prostatectomy," "robotic cystectomy," and "robotic nephrectomy, " following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Figure 1).A total of 22 studies were identified from the initial search.After title and abstract screening (2 duplicates, 1 non-English, 3 not associated or not mentioning robotic-assisted procedures in the title or abstract), 16 studies were included in the review.Original studies or reviews investigating the association of frailty and robotically-assisted urological oncology procedures were included, either in comparison to laparoscopic and open surgery or to non-frail patients.Case reports or studies that did not include robotically-assisted procedures in the frail were excluded from our review.A non-systematic narrative review was performed.

Results
Most studies included patients who underwent robotic radical prostatectomy (12 studies), with only 4 studies investigating the association of frailty with the outcomes of robotic partial nephrectomy (RPN) and robotic radical cystectomy (2 studies each).No studies to assess the correlation between frailty and robotic radical nephrectomy, robotic partial cystectomy, or robotic radical nephroureterectomy were found (Table 1).
All the available studies used the Clavien-Dindo classification of complications, with serious complications considered as those with a score ≥3.Most studies included in the literature review were systematic reviews with or without meta-analysis and narrative reviews.Also, case-control studies and retrospective studies were retrieved from our search, and only 1 prospective study.No randomized control trials were identified.
The available studies show that frail patients significantly benefit from robot-assisted urological oncological procedures in comparison to open surgery.Nevertheless, frailty is associated with a higher risk of postoperative complications and worse outcomes than for nonfrail individuals and with higher costs for the health care system.

Robot-Assisted Radical Cystectomy and Frailty
Considered to be the most severe oncological procedure in urology, RARC is associated with the highest morbidity and mortality rates of all other robotic urological procedures.Hence, it is of utmost importance to investigate the procedure's safety in the population of frail individuals.The percentage of frail patients undergoing RARC in the available studies was 14% (range 9%-18%), while the non-frail RARC percentage was 17% (8%-24%). 1,2Frail patients undergoing RARC benefited from a shorter length of stay (LOS) (median 8 vs. 9 days, P < .001), in comparison to those having open surgery.Regardless, frailty was significantly associated with a higher risk of postoperative complications in comparison to non-frail patients, as well as higher chance of Intensive care unit admittance.Total costs were also significantly higher among frail RARC patients, with frailty being a more important predictor of additional costs than the Charlson Comorbidity Index.Most importantly, frail patients were found to have 2 times higher in-hospital mortality than nonfrail patients (3% vs. 1.5%,P < .05).The most accurate indexes to assess the risk of postoperative complications in frail patients undergoing robotic radical cystectomy were found to be the Johns Hopkins indicator (JHI) and the simplified frailty index (sFI).However, the most commonly used index was the modified frailty index, a reduced 11-item index of the Canadian Study of Health and Aging Frailty Index (CSHA-FI). 1,2

Robot-Assisted Partial Nephrectomy and Frailty
In comparison to open surgery, RPN is associated with several advantages for frail patients.In total, RPN, which is the chosen technique in 13% to 40.4% of the patients, has shown lower overall risk for postoperative complications in the frail population (35.3% vs. 48.3%),major complications Clavien-Dindo ≥3 (12.4% vs. 20.4%),as well as lower rates of blood transfusion and shorter LOS, but also increased total hospital costs (P < .001). 3,4vertheless, when compared to the non-frail population, frailty has been found to be significantly associated with a higher rate of complications after RPN.Furthermore, frail patients had a higher likelihood of manifesting postoperative acute kidney insufficiency, since their renal function permanently decreased over time, without improvement during the follow-up period as seen with the nonfrail.In addition to this, frailty was implicated with higher rates of other-cause mortality [hazard ratio: 1.67, 95% CI, 1.05-2.66;P = .02],although cancer-specific mortality rates did not differ (P = .3).In other words, the risk of death from other causes is much higher than the mortality from renal cell carcinoma in the frail population.Thus, frail patients should be carefully evaluated and consulted about the risks and benefits of RPN before choosing to proceed to minimal invasive treatment. 4

Robot-Assisted Radical Prostatectomy and Frailty
The most studied robotic urological procedure on frail individuals is robotic radical prostatectomy, and the most widely used frailty index to evaluate these patients is the Geriatric 8 (G8) screening tool. 5

MAIN POINTS
• Higher rates of robot-assisted urological oncology procedures, in the population of elderly and frail patients are performed in the last decade.

• We investigate the safety of robotically-assisted urological procedures in frail patients and their outcomes in comparison to open surgery. • The aim of this review was to compare and suggest the most
effective preoperative screening tools to assess these patients' fitness to tolerate minimal invasive urological surgery.
It is well established that comorbidities such as cerebro-cardiovascular disease or chronic respiratory disease and frailty indexes like the G8 <14 are significant contra-indicators for offering surgical treatment with RARP. 5 In addition to this, frailty is a proven cause of conversion to open during minimally invasive radical prostatectomy (laparoscopic or robotic), although it does not seem to affect the postoperative quality of life of the patients. 6,9rthermore, it is suggested that frailty and older age (>75) do not affect the oncological outcomes and patient reported outcomes, such as return to continence for patients undergoing RARP, with the exception of erectile function which is negatively affected by senior age. 9,10,11However, frailty is associated with an increased risk of postoperative complications, especially severe complications (Clavien-Dindo >IV) and 30-day mortality after RARP, as well as higher rates of moderate-to-severe postoperative pain. 12,13,14e increased experience of the surgical community in performing robotic procedures during the last decade has subsequently increased the number of frail individuals who undergo RARP for prostate cancer. 15This tendency to perform RARP in more frail patients also derives from indications of high rates of misclassification of these patients between clinical vs. pathological PCa burden. 16gardless of the cause for more frail men undergoing RARP, it is well proven that these patients are also at a higher risk of experiencing postoperative complications, with the rates not being different between open and RARP. 17nce, it is of utmost importance that frail patients are carefully assessed on their fitness to tolerate surgery.The Vulnerable Elders Survey-13 (VES-13) and G8 are accurate and easy-to-use geriatric screening tools that can successfully determine the surgical fitness of frail patients and could potentially substitute life expectancy as the main criterion for choosing RARP as the preferred treatment option. 18

Discussion
It has recently been proven that frailty is an important parameter that affects the surgical outcome of major oncological procedures in urology. 19The most recent guidelines of the European Association of Urology for urogenital malignancies, such as for prostate cancer, kidney cancer, and muscle-invasive bladder cancer, recommend a preoperative patient assessment concerning their fitness to tolerate oncological procedures, such as radical prostatectomy, partial nephrectomy, and radical cystectomy respectively. 20,21,22ss than a decade ago, the first studies investigating the association of minimally invasive urological surgery with frailty were published. 12][5][6][7][8][9][10][11][14][15][16][17][18] As a consequence, no previous reviews are available to summarize the evidence concerning the outcomes of the most common robot-assisted urological procedures in frail patients, although these minimally invasive oncological operations have increased during the last decade.
In this review article, we present for the first time in the literature, to the best of our knowledge, the outcomes and safety of the major oncological robot-assisted urological procedures in frail patients, as well as the most accurate frailty indexes for the preoperative patient assessment.
A study by Rosiello et al 3  frail patients are at an increased risk of complications after partial nephrectomy (open or robotic), non-reversible acute kidney injury, and other-cause mortality.
Besides, Abou Heidar et al 15 showed that RARPs have also significantly increased in frail and comorbid patients from 2011 to 2019. 15More specifically, patients with 5-item frailty index ≥2 showed an increase from 9.4% in 2011 to 12.5% in the year 2019 (P < .001),while patients with metabolic syndrome index = 3 also showed a rise from 4.1% in 2011 to 6.1% in 2019 (P < .001).In addition, patients with an American Society of Anesthesiologists' score ≥3 also showed an increase from 32.8% in 2011 to 42.4% in 2019 (P < .001).Another study showed that 36% of RARP patients had a G8 score ≤14. 23is increase in frail patients undergoing RARP did not result in higher rates of major morbidity or mortality, according to the authors, although this could be explained in part by the added experience of the surgeons. 15Nevertheless, a recent meta-analysis showed that frailty is associated with a higher risk of severe postoperative complications (≥Clavien-Dindo IV) and all-cause mortality, regardless of the approach being open or robot-assisted. 17 a population-based retrospective study by Palumbo et al 2 it was shown that, as with RARP and RPN, RARC has been offered to a higher rate of frail patients (estimated annual percentage changes +27.1%,P < .001),from 0.2% in 2008 to 7.89% in 2015.Frail patients who underwent RARC mainly benefited from a shorter LOS (LOS 8 vs. 9 days, P < .001).Apart from this, RARC was associated with higher costs among both frail and non-frail.
Several frailty indexes have been used to preoperatively assess RARC patients; however, a systematic review by Ornaghi et al 1 found that the JHI and the sFI, an easier-to-use 5-item index based on the CSHA-FI, are the most reliable for identifying patients at higher risk of experiencing postoperative complications. 1 Similarly, the G8 screening tool is one of the most commonly used frailty indexes for patients undergoing RARP. 5,16,18,21The G8 scores range from 0 to 17 and the most used cutoff for frailty is ≤14, with a 65.2% sensitivity and 95.7% specificity for detecting vulnerable prostate cancer patients. 24Alternatively, the VES-13 is an easyto-use screening tool that can predict mortality in patients with prostate cancer. 25,26In patients who received androgen deprivation treatment, the sensitivity and specificity of VES-13 in predicting adverse events were 72.7% and 85.7% respectively, 27 when compared to the Comprehensive Geriatric Assessment, which is the gold standard for assessing the health status of patients but is time-consuming and requires the necessity for several types of experienced physicians, such as geriatrists, urologists, and physical therapists. 18mitations of this review article include its non-systematic design and the small number of available studies, most of which were retrospective or observational.Prospective studies with a larger number of patients will standardize frailty indexes and improve decisionmaking for robotic surgery, for both the multidisciplinary team of physicians and the patients' family.
In conclusion, most studies are in agreement that although robotassisted procedures improve outcomes for frail patients and reduce perioperative morbidity and mortality, frailty is still a significant risk factor that leads to more severe complications than in the non-frail population.

Conclusion
Frail patients can benefit from robot-assisted urological procedures, but are more susceptible to worse postoperative outcomes and a higher risk of severe complications than the non-frail.As a result, routine preoperative frailty assessment is of utmost importance, using standardized indexes such as the JHI and sFI for RARC and RPN and the G8 screening tool for RARP, in order to safely choose patients who are fit for minimally invasive surgery.

Declaration of Interests:
The authors have no conflict of interest to declare.

Funding:
The authors declared that this study has received no financial support.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses Flow Diagram.